1. Field of the Invention
The invention relates to a device, in particular to a sample preparation device for the quantitative analysis of a drug and/or metabolite profile in a biological sample. Moreover, the invention relates to an insert for such a device, an internal standard, and to a kit containing the device. Furthermore, the invention also relates to an apparatus containing the device, and to a method for the quantitative analysis of a drug and/or metabolite profile in a biological sample employing the device.
2. Description of the Related Art
Metabolomics is generally defined as the analysis of a substance or group of substances necessary for or taking part in a particular metabolic process in a human or animal body. It's also known as the metabolome analysis. Metabolomics is an evolving discipline that studies unique chemical fingerprints reflecting metabolic changes related to disease onset and progression. Metabolite profiling, an area within metabolomics, measures small molecules or metabolites, contained in a human cell, tissue or organ, which are involved in primary and intermediary metabolism. The biochemical information resulting from metabolite analysis reveals functional end-points associated with physiological and pathophysiological processes, influenced by both genetic predisposition and environmental factors, such as nutrition, exercise or medication (Harrigan, G. G. & Goodacre, R. (2003) Metabolic profiling: Its role in biomarker discovery and gene function analysis. Kluwer Academic Publishers, Boston/Dordrecht/London; Schmidt, C. (2004), Journal of the National Cancer Institute, 96, 732-734; Raudys, S. (2001) Statistical and neural classifiers, Springer-Verlag, London; Daviss, B. (2005) The Scientist, 19, 25-28). Metabolite profiling in combination with data mining approaches have the potential to revolutionize clinical diagnosis and drug development. In particular, big pharma companies are under continuous pressure to discover new targets and novel, more efficacious and safer compounds, and expedite biomarker and drug discovery, and generally lower costs of pharmaceutical development. Therefore they rely increasingly on biotech companies to fill this innovative gap and future pipelines. In this context, innovative bioanalytical and data mining techniques will play a fundamental role in saving costs by reducing time to market and drug attrition rates.
Recently, due to significant advances in high-throughput technologies, a wider set of the human metabolome—a thus far largely unexplored source of bioinformation—is now accessible (Beecher, C. (2003). In Harrigan, G. G., Goodacre, R. (Ed). Metabolic profiling: Its role in biomarker discovery and gene function analysis (pp. 311-319). Kluwer Academic Publishers, Boston/Dordrecht/London; Dunn, W. B., Bailey, N. J. & Johnson, H. E. (2005) Analyst, 130, 606-625). Statistical comparison of metabolite profiles can expose multivariate patterns that have the potential to revolutionize the health care system by specifically capturing latent warning signs of up-coming diseases before any disease symptoms show up. Early disease screening and prevention, opposed to late disease detection and expensive therapeutic interventions, is probably the primary solution to affordable health care coverage in the future. By definition, these so called biomarkers are “objectively measured indicators of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention, and intend to substitute for a clinical endpoint (predict benefit or harm) based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence” (Biomarkers Definitions Working Group. (2001) Clinical Pharmacology and Therapeutics, 69, 89-95). Interest in the discovery of novel biomarkers originates from their broad range of potential applications and fundamental impact on pharmaceutical industry dynamics and current health care sector principles. Successful implementation of biomarkers in drug discovery can reduce the time and cost of drug development while the application to molecular diagnostics will improve patient compliance in clinical settings and reduce unnecessary costs resulting from false diagnosis in addition to late disease detection (Stoughton, R. B. & Friend, S. H. (2005), Nature Reviews Drug Discovery, 4, 345-350; Morris, M., & Watkins, S. M. (2005), Current Opinion in Chemical Biology, 9, 407-412; McCandless, S. E. (2004), Primary Care, 31, 583-604).
Qualitative and quantitative metabolite profiling technologies include a range of advanced analytical and data processing tools, with the objective of utilizing potential markers as a result of comparison of small molecule components of biological systems. Tandem mass spectrometry (MS), for example, detects hundreds of metabolites simultaneously from micro liter quantities of biological samples, such as whole blood, serum, plasma, urine or other body fluids from minute amounts, with high precision and sensitivity (Roschinger, W., Olgemoller, B., Fingerhut, R., Liebl, B. & Roscher, A. A. (2003), European Journal of Pediatrics, 162 (Suppl 1), S67-76; Strauss, A. W. (2004), J Clin Invest 2004; 113:354-356; Kaltashov, I. A. & Eyles, S. J. (2005), Mass spectrometry in biophysics: Conformation and dynamics of biomolecules, Wiley). Quantification is achieved by reference to a wide range of appropriate internal standards.
For example, WO 03/005628 describes a method for generating, viewing, interpreting and analyzing a quantitative database of metabolites. Further, U.S. Publication 2002/0009740 describes methods for drug discovery, disease treatment and diagnosis using metabolomics. U.S. Pat. No. 6,455,321 describes a method for interpreting tandem mass spectrometry data for clinical diagnosis. U.S. Pat. No. 6,258,605 describes an analytical method to screen the newborn populations' acylcarnitine and amino acids from blood samples. U.S. Pat. No. 6,627,444 describes a sampling device to aid in calibrating a field instrument.
Furthermore, U.S. Publication 2006/0057554 describes a sample collection device that includes a support bearing an inert absorbing matrix for a fluid sample, wherein the matrix preferably comprises pre-calibrated selected inorganic analytes as internal standards. Moreover, U.S. Publication 2003/0199102 describes a testing tray comprising multiple cells, wherein the cells contain a tried internal standard. The testing tray is for conducting multiple of tests on a biological fluid.
In order to handle the biological samples to be evaluated, further sample devices are known in the related art. For example, Tanaka et al., Clinical Chemistry 47:10, 1829-1835 (2001) describes a microvolume blood-sampling device with low hemolysis and high consistent yield of serum components.
However, the known sample devices show several disadvantages. In particular, the device described in U.S. Pat. No. 6,627,444 is designed for releasing calibration compounds by way of heating only. It is also designed solely for calibrating an instrument.
Other devices like the device disclosed in U.S. Publication 2006/0057554 fail to use identical organic compounds labelled with stable isotopes preimbedded in a specially designed device for extracting and derivatising.
As a result, there is a need to provide for an improved, highly efficient and reliable quantitative analysis of a drug profile or a metabolite profile in a biological sample, i.e., of concentrations of primarily endogenous, but not excluding exogenous compounds like drugs and metabolites thereof and metabolites from various biological samples.